Transcript PowerPoint Presentation - Spinal Cord Injury Research 2003

Bases for Hope in Spinal
Cord Injury Research
Wise Young, Ph.D, M.D.
W. M. Keck Center for Collaborative
Neuroscience, Rutgers University,
Piscataway, New Jersey
State-of-the-Art 1995
• Acute and Subacute Therapies
– Methylprednisolone is neuroprotective (NASCIS, 1990)
– GM1 improves locomotor recovery in humans (Geisler, 1991)
• Promising Therapies
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–
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IN-1 antibody stimulates regeneration in rats (Schwab, 1991-)
Fetal tissue transplants survive in animals (Reier, 1992-)
Functional regeneration of neonatal spinal cords (Kawaguchi, 1994-)
Neurotrophin-secreting fibroblast transplants (Tuszynski, 1994-)
• Spasticity and Pain Therapies
– Intrathecal baclofen for severe spasticity
– Tricyclic antidepressant amitryptiline (Elavil) for neuropathic pain
– 4-aminopyridine may improves function in some people with chronic
spinal cord injury (Hansebout, 1992-)
Surgical Therapies
• Stabilization & decompression
– Stabilization
• Anterior and posterior plates
• Titanium cage & other
vertebral fusion methods
– Delayed decompression
restore function (Bohlman)
– Untethering spinal cord
improves function
– Adcon gel and other methods
to prevent epidural scarring
• Syringomyelic cysts
– Remove subdural adhesions
– Restore CSF flow
– Dural grafts to reduce
incidence of re-adhesion
• Urological procedures
– Suprapubic catheterization &
Ileal conduits (Mitrafanoff)
– Stents and artificial sphincters
for bladder and bowel
• Peripheral nerve bridging
– Implanting avulsed roots or
nerves into cord for
• Muscle reinnervation
• Reduce neuropathic pain
• Bladder reinnervation
– Peripheral nerve bridging
• Bridging spinal accessory,
intercostal, and ulnar nerves
to phrenic, sciatic, pudendal,
and other peripheral nerves
• End-to-side anastomoses
Medical Therapies
• Subacute Therapies
– Monosialic ganglioside (GM1)
accelerates motor recovery
(Geisler, 1999)
• Neuropathic Pain
– Intrathecal drugs
– Anti-epileptic drugs:
• High-dose Neurontin
(gabapentin), i.e. 2000-4000
mg/day may produce stable
relief of neuropathic pain
• Carbemapazine
– Glutamate receptor blockers:
• Dextromethorphan
• Oral ketamine
– Cannabinoids
– Opioids
• Anti-spasticity therapies
– Bladder spasticity
• Intravesicular ditropan
• Intravesicular capsaicin
– Tizanidine
• Alpha adrenergic receptor
agonist, similar to clonidine
– Oral 4-aminopyridine
• Reduces pain & spasticity
(Hayes, et al. 1998)
• May improve bladder, bowel,
and sexual function
• May improve motor and
sensory function in a third of
patients with chronic SCI.
• 4-AP may be the first drug
that reduces spasticity without
causing weakness.
Rehabilitative Therapies
• Functional electrical
stimulation (FES)
– Diaphragmatic pacers
– Bladder stimulators
• Brindley sacral stimulation
• Medtronics stimulator for
incontinence
• Praxis stimulator
– Hand stimulators
• Ness hand stimulator
• Freehand
– FES handcranks & bicycles
– Leg/walking stimulators
(Parastep)
• Reverse learned non-use
– Forced-use training
• Short periods of inactivity
induces “learned non-use”
• Intensive use restores
motor function in chronic
hemiplegia (Taub, 2000)
– Biofeedback therapy
– Supported treadmill
ambulation training
• Wernig, et al. (Germany)
• Dobkin, et al. (UCLA)
– Robotic exercisers
• Lokomat, Ambulator
• Glider (manual)
Regenerative Therapies
•
Axonal growth inhibitor blockade
•
– Nogo antibody IN-1 (Schwab, et
al. 1990-2003).
– Rho inhibitor (McKerracher, 2001)
– Chondroitinase (Bradbury, 2002)
– Nogo receptor blockers
(Strittmatter, 2001-2003)
•
•
Therapeutic vaccines
– Spinal cord homogenate vaccine,
(David, et al., 1999); Nogo/MAG
vaccines (Schwartz, et al. 2003)
•
– Olfactory ensheathing glia
• Adult olfactory bulb (RamonCuetos, 2000);
• Nasal mucosa (Lu, et al. 2002)
• Fetal olfactory bulb (Huang, et
al.2003)
– Bone marrow stem cells (Black, et
al. 199; Barros, 2003)
– Neural stem cells (Okano, et al.),
radial glia (Grumet, et al. 2003)
Purine nucleotides
– Modified guanosine AIT-082
(Neotherapeutics)
– Inosine (Benowitz, et al. 1999)
– Adenosine (Chao, et al, 2000)
Alternating electrical currents
– Borgens, et al. 1997
Cell Transplants
•
Growth Factors
– FGF+GDNF (Cheng, et al.1996,
2003),
– Combination neurotrophins (Xu,
2001)
– cAMP & Rollipram (Filbin, 2001)
– L1 (Roonprapunt, et al., 2003)
– Erythropoietin (Gorio, et al, 2003)
Remyelinative Therapies
•
Immunoglobulin therapy
– M1 antibody to stimulate
remyelination (Rodriguez, 1996-)
– Copaxone (copolymer 2) improves
recovery in rats (Schwartz, et al.
2001)
•
Oligodendroglial growth factors
– Neuregulin (GGF2)
Olfactory ensheathing glia (OEG)
– Transplanted OEG cells
remyelinate axons in the spinal
cord (Kocsis, et al. 1999)
•
Schwann cells
– Schwann cell invasion into cord
(Blight, 1988; Blakemore, 1990)
– Schwann cell transplants and
bridges (Bunge, et al. 1993-2003)
– Peripheral nerve transplants (Kao)
Oligodendroglial cell transplants
– Endogenous oligodendroglial
precursor cells (Gage, 1999)
– O2A precursor cells remyelinate
spinal axons (Blakemore, et al.
1996-)
– Embryonic stem cells produce
oligodendroglial precursors that
remyelinate injured spinal cords
(McDonald, 1999).
•
•
•
Stem cells
– Mouse embryonic stem cell
myelinate rat spinal cords
(McDonald,et al 2000)
– Porcine fetal stem cells (Diacrin
clinical trial)
– Human fetal stem cells (Clinical
studies in Moscow & Novosibirsk)
Completed Clinical Trials
• The National Acute Spinal Cord Injury Study III
– Multicenter trial compared about 500 patients treated with a single bolus
of methylprednisolone (MP) and then randomized to 24-hour or 48-hour
course of 5.4 mg/kg MP or a 48-hour course of tirilazad mesylate.
– The 24-hour MP course was best when given within 3 hours and 48hour MP was best when patients are treated >3 hours after injury
• Fidia monosialic ganglioside (GM1, Sygen) trial
– Over 40 U.S. trial centers, 800 patients treated with MP and then
randomized to 6 weeks of GM1 or 6 weeks of placebo.
– Results suggest that GM1 may accelerate recovery but did not change
the extent of recovery at 6-12 months after injury.
• Fetal spinal cord transplants for syringomyelia
– Gainesville, Rush Presbyterian in Chicago, Karolinska in Sweden,
Russia (Moscow, Novosibirsk, Kiev), and China (Guangzhou, Beijing)
• AIT-082 (Neotrofin) therapy of spinal cord injury
– Neotherapeutics: Ranchos Los Amigos, Gaylord, Craig, Jefferson
Current Clinical Trials
• Subacute SCI
– Activated macrophage transplants for subacute SCI (Proneuron)
• Tel Aviv, Erasmus (Brussels), Craig Hospital (Denver), Mt. Sinai (NY),
Kessler Rehabilitation Center (NJ)
– Alternating current electrical stimulation for subacute SCI
• Purdue University in Indiana
• Chronic SCI
– Fampridine SR (4-aminopyridine) for chronic SCI
• Acorda: Phase 3 trial in 82 U.S. & Canadian SCI Centers
– Porcine neural stem cell transplants for chronic SCI
• Diacrin: Albany Med. Center and Washington University in St. Louis
– Olfactory ensheathing glial (OEG) transplants
• Brisbane (adult OEG), Lisbon (nasal mucosa), Beijing (fetal OEG)
– Bone marrow stem cell transplants
• University of Sao Paulo (Barros)
Emerging Promising Therapies
• Chondroitinase
– Chondroitin-6-sulfate proteoglycan (CSPG) inhibit axonal growth in
spinal cord (Silver, et al., 1993)
– Chondrotinase ABC (Chase ABC) is a bacterial enzyme that breaks
down CSPG and stimulates regeneration (Bradbury, et al. 2002)
• Glial-derived neurotrophic factor (GDNF)
– A growth factor produced by glia, GDNF appears to be neuroprotective
(Cheng, et al. 2002) and stimulates axonal growth (Xu, et al., 2003).
– GDNF is currently in clinical trial for Parkinson’s disease.
• Olfactory ensheathing glia (OEG)
– These specialized cells originate in nasal mucosa, migrate in olfactory
nerves to olfactory bulbs, and may explain ability of adult olfactory
nerves to regenerate (Doucette, et al., 1991)
– OEG cells stimulate regeneration and remyelination when transplanted
into spinal cord (Raisman, et al., Ramon-Cueto, et al., Kocsis, et al., and
others from 1998-2003).
Olfactory Ensheathing Glia
• Fetal OEG cells
– Bipolar (migrating)
– Multipolar (guidance?)
– “Fried egg” (ensheathing)
• Markers
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Laminin & L1 CAM
Nestin
GFAP
P75 (NGF receptor)
• Roles in regeneration
– Growth
– Guidance
– Myelin
OEG Clinical Trials
• Lisbon (Portugal)
– Carlos Lima in Lisbon transplanted nasal mucosa into spinal
cords of over 10 patients with chronic spinal cord injury
• Brisbane (Australia)
– Tim Geraghty and Alan McKay-Sims in Brisbane cultured and
transplanted 15 million OEG cells from nasal mucosa into four
patients with chronic spinal cord injury
• Beijing (China)
– Hongyun Huang in Beijing cultured OEG from fetal olfactory bulb
and transplanted into over 300 patients with chronic spinal cord
injury
• Novosibirsk (Russia)
– Samuiel Rabinovich has transplanted mixtures of OEG and
neural stem cells into 15 patients with chronic spinal cord injury
Beijing OEG Clinical Trial
• Subjects
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–
–
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171 patients
age 2-64 (mean 34.9) years
139 male and 32 female,
6 months to 18 years after
injury
Age
n
Motor
Touch
Pin
≤20
9
5.2
±4.8
13.9
±8.1
11.1
±7.9
21-30
54
8.6
±8.0
15.5
±14.3
17.2
±14.3
31-40
60
8.3
±8.8
12.0
±14.4
13.2
±11.8
41-50
34
5.7
±7.3
14.1
±18.5
13.6
±13.9
>51
14
8.2
±7.6
24.8
±25.3
25.4
±24.3
• Surgery
– Block laminectomy
– 500,000 fetal OEG injected
above and below the injury
site
– Tight dural closure
Huang, et al. (2003). Chin. Med. J. 116:1488-91
Other Clinical SCI Studies
• NIH Clinical Trial to assess use of supported treadmill ambulation
training to reverse learned non-use
• Spinal cord L2 stimulation to activate locomotor pattern generator
– Hermann in Tucson and Dimitrijevic in Vienna
• Experimental surgical approaches
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–
–
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Fetal stem cell transplants (Moscow, Novosibirsk, Beijing)
Peripheral nerve bridging to spinal cord (Brunelli in Brescia)
Peripheral nerve bridging to bladder and muscle (Zhang in Shanghai)
Bridging spinal cord injury site with peripheral nerves & growth factor
cocktail (Cheng in Taiwan)
– Untethering, peripheral nerve transplants, omentum transplant,
hyperbaric oxygen, and 4-aminopyridine (Carl Kao in Ecuador)
– Omentum transplants (U.S., Cuba, China, and Italy)
– Shark embryonic transplants (Tijuana)
Planned Clinical Trials
• IN-1 (anti-Nogo antibodies)
– Novartis
• Nogo receptor blockers
– Biogen
• IgM kappa antibodies
– Acorda
• Inosine
– Boston Life Science
• Cethrin (C3 rho inhibitor)
– BioAxone
• Bone marrow stem cells
– Neuronyx
• Fetal neural stem cells
– Okano, et al. Keio University
• Umbilical cord blood stem cells
– Stemcyte
• Chondroitinase ABC
– Acorda Therapeutics,
Seikagaku, and others
• Glial derived neurotrophic
factor (GDNF)
– Amgen in San Diego
• Erythropoietin
– Johnson & Johnson
Generations of SCI Therapies
•
First Generation Therapies
– 4-Aminopyridine (Acorda)
– Growth stimulators
• GM1 (Fidia)
• AIT-082 (Neotherapeutics)
• AC electrical currents (Purdue)
– Cell transplants
• Fetal spinal cord transplants (UFG)
• Macrophages (Proneuron)
• Fetal stem cells: porcine (Diacrin),
human (Russia, China)
• Peripheral nerve grafts (Taiwan)
• Olfactory ensheathing glia (Beijing),
nasal mucosa autograft (Lisbon),
cultured nasal OEG (Brisbane)
• Neurotrophin-secreting fibroblasts
– Locomotor training
• Supported ambulation treadmill
training (Bonn, Zurich, UCLA, etc)
• Locomotor FES (Arizona, Vienna)
•
Second Generation Therapies
– Immune therapies
• M1 antibody (Acorda)
• Copolymer Copaxone (Teva)
– Growth inhibition blockers
•
•
•
•
•
Humanized IN-1 (Novartis)
Rollipram (PDE-4 inhibitor)
C3 Rho inhibitor (BioAxone)
Chondroitinase ABC (Seikagaku)
Nogo receptor blocker (Biogen)
– Growth factors
• Neurotrophin (Regeneron)
• Inosine (BLSI)
• Neuregulins (Acorda)
– Cell Transplants
•
•
•
•
Bone marrow stem cells
Umbilical cord blood stem cells
Genetically modified stem cells
Enteric glial stem cells
Third Generation Therapies
• Combination therapies
– Regenerative
•
•
•
•
Bridging the injury site
Growth factors
Overcoming inhibition
Guiding axons to target
– Remyelinative
• Stimulating remyelination
• Remyelinating with Schwann,
OEG, O2A, embryonic stem
cells
– Restorative
•
•
•
•
4-aminopyridine
Biofeedback therapy
Forced use therapy
Activity-induced plasticity
• New therapies
– Vaccine
• Regenerative vaccines
• Neuroprotective vaccines
• Remyelinative vaccines
– Stem cells
• Neuronal replacement
• Reversing atrophy
• Replacing motoneurons
– In vivo gene therapy
• Gene therapy to express
neurotrophins and other
growth factors
• Cell adhesion molecules to
direct axonal growth
• Ephrins and sonic hedgehog
to stimulate axonal growth
Sources of Stem Cells
• Embryonic stem cells
–
–
–
–
In vitro fertilized eggs
Cloned eggs
Parthenogenic eggs
Eggs from embryonic stem
cells
• Fetal stem cells
– Fetal neural stem cells
– Germ cell line stem cells
– Many other tissues of
fetuses contain large
numbers of stem cells.
• Umbilical cord
– Neonatal blood
– Placenta, umbilical vein
• Adult stem cells
– Neural stem cells
• Hippocampus
• Olfactory bulb
• Spinal cord
– Mesenchymal stem cells
•
•
•
•
Bone marrow stem cells
Nasal mucosa stem cells
Peripheral blood
Skin and other organs
– Enteric glia (appendix)
Stem Cells
Neurosphere
Nestin stain
BRDU stain
Restorative Principles
• “Complete” spinal cord injury does not mean transection
– Severance or transections of the cord are very rare
– <10% of axons can support substantial functional recovery
• Accelerating and extending recovery processes
– Continued recovery in chronic SCI over many years
– Spontaneous regeneration may occur in some people
• Surviving and regenerating axons need to be myelinated
– 4-aminopyridine improves conduction
– Cell transplantation to remyelinate spinal axons
• Spinal cords are capable of remarkable “plasticity”
– Detailed specificity of reconnection may not be necessary
– Local sprouting can restore functions across the midline
•
Reversing learned “non-use”
– Even a short period of non-use can turn off circuits
– Intensive “forced-use” exercise can restore function
Preparing for Recovery
• Avoid unnecessary irreversible
surgical procedures, e.g.
• Relieve causes of continuing
spinal cord damage
– Dorsal root rhizotomies, spinal
cord transections
– Surgery that sacrifice major
peripheral nerves
– Decompression
– Untethering cord
– Reduce syringomyelia cysts
• Prevent muscle and bone
atrophy
– Titrate anti-spasticity drugs
such as baclofen so that not
all spasticity is eliminated.
– Do standing and walking
exercises
– Use functional electrical
stimulation (FES) to maintain
and build up muscles
• Reverse learned non-use
– Physical therapy
– Activity-induced plasticity
• Swimming and hydrotherapy
• Weight supported treadmill
ambulation training
– Biofeedback therapy
– L2 locomotor pattern
generator stimulation
Conclusions
• In 1995, only one therapy (methylprednisolone)
improved recovery when given after spinal cord injury.
Several therapies showed promise in laboratory studies.
• In eight years, advances in surgical and medical
therapies have revolutionized spinal cord injury care.
Intensive training may improve locomotor recovery.
• Several clinical trials have shown limited results (fetal
spinal cord transplants, GM1) but other ongoing trials
may yield positive results (4-AP, OEG, AC currents)
• Many regenerative and remyelinative therapies that
improve functional recovery in animals have started or
will soon start in clinical trials.